1. Field of the Invention
This invention is directed to new mitomycin derivatives having good anti-tumor activity while at the same time demonstrating reduced bone marrow toxicity as compared to the parent compounds.
The mitomycin derivatives of the present invention are characterized by thiourea substitution at position 1a and, additionally, glycosyl substitution at either the 1a or 7 position.
2. Brief Description of Related Art
The mitomycins are compounds corresponding to the general formula (I): ##STR1##
Mitomycins A, B and C are related to one another as set forth in Table 1 below, the designations X Y and Z being those of formula (I).
TABLE I ______________________________________ Mitomycin: X Y Z ______________________________________ A --OCH.sub.3 --OCH.sub.3 --H B --OCH.sub.3 --OH --CH.sub.3 C --NH.sub.2 --OCH.sub.3 --H ______________________________________
Mitomycins are derived from mitosane compounds which, generically have the following skeleton II: ##STR2## The mitosanes are formed during the cultivation, under artificially controlled conditions, of the microorganism Streptomyces caespitosus in a liquid nutrient medium. After separating the resulting mycellium, for example, by filtration, from the obtained culture broth, the various mitomycins may be isolated from the latter by active carbon or preferably non-ion exchange resin adsorption, organic solvent extraction or chromatography on alumina, as disclosed by U.S. Pat. No. 3,660,578 to Hata et al.
The mitosanes are acknowledged as excellent antibiotics but are disadvantageous in that they are toxic to human blood (see U.S. Pat. No. 3,450,705 to Matsui et al.). The relatively highly toxic nature of the compounds has prompted prior art synthesis of numerous mitomycin derivatives and analogues in an attempt to secure compounds having equal or enhanced antibiotic activity but lesser toxicity than the naturally occurring mitomycins.
In the above noted U.S. Pat. No. 3,450,705 to Matsui et al., there are disclosed mitomycin compounds substituted at the 7 position with amino, lower alkyl amino, phenyl amino, or pyridyl, and substituted at the 1a position with haloalkanoyl, halobenzoyl, nitrobenzoyl, alkenoyl, acetyl glycyl, sorbyl or acetyl methionyl.
U.S. Pat. No. 3,558,651 to Matsui et al. discloses mitosane derivatives which are 1a-acyl-7-acyloxy-9a-methoxy compounds.
Certain mitomycins and mitomycin derivatives possess a degree of in vivo anti-tumor activity as well, as reported by Oboshi et al., GANN, 58: 315-321 (1967); Usubuchi et al., GANN, 58: 307-313 (1967); Matsui et al., J. Antibiotics, XXI, No. 3: 189-198 (1968); Japanese Patent No. 68 06 627 to Mastui et al. (as reported in Chem. Abstracts, Vol. 69, 86986K (1968)); and Cheng et al., J. Med. Chem., 20, No. 6: 767-770 (1977)
As disclosed in Mitomycin C: Current Status and New Developments, Carter et al., Eds., Academic Press, New York (1979), while mitomycin C is active against a relatively broad spectrum of experimental tumors, clinical practice restricts its use to certain carcinomas owing to its toxicity and particularly its myelosuppressive effects.
Recent pre-clinical and clinical studies of mitomycin C have confirmed its activity in a variety of murine and human neoplasms, but its clinical use has been limited by the severe, delayed bone marrow toxicity of the compound, and its narrow therapeutic index (Goldin, A. et al., NCI-EORTC Symposium on Mitomycin C, Brussels, Belgium, 1981). In that same reference, Goldin et al. reported preclinical studies which indicated that animal studies are predictive for the clinical toxicities of mitomycin C. In mice, rats, cats, dogs, and rhesus monkeys, the toxicities caused severe bone marrow depression and gastrointestinal damage, and were delayed in onset.
Trials initiated at the Lombardi Cancer Research Center of Georgetown University (Schein, P. S. et al., "Mitomycin C: Current Status and New Developments, pp. 133-143, Carter et al., Eds., Academic Press, New York (1979)) demonstrated that a combination of three drugs, 5-fluorouracil, adriamycin, and mitomycin C, was effective in the treatment of patients with advanced gastric and colorectal cancer. The regimen incorporated mitomycin C administration in a single dose schedule every two months, to decrease the treatment-limiting delayed myelosuppressive effects of the compound.
As disclosed by Remers, U.S. Pat. No. 4,268,676, numerous semi-synthetic analogues of mitomycin C have been prepared in the hope of obtaining compounds with improved therapeutic properties, especially anti-tumor properties. These analogues have involved substitution on the aziridine ring, carbamoyl, or acyl group substitution on the hydroxymethyl side chain, and replacement of the 7-substituent in the quinone ring with other functional groups, especially substituted amines. However, as disclosed by Remers, none of these analogues has emerged as a clinical agent, with the possible exception of the 7-hydroxy analogue of mitomycin C, which has been involved in a recent study in Japan. This analogue is asserted to be less leukopenic than mitomycin C, although it is also much less potent. Further mentioned by Remers are totally synthetic mitomycin analogues of the mitosane type (Mott et al., J. Med. Chem., 21: 493 (1978)), prepared mainly for their antibacterial activity.
Kinoshita, S. et al., J. Med. Chem., 14, No. 2: 103-112 (1971), reported the results of studies of several derivatives of mitomycin substituted in the 1a, 7, and 9a positions. Included in this study were compounds substituted at the 1a position with sulfonyl, ortho-substituted benzoyl, and acyl derivatives.
Iyengar, B. et al., J. Med. Chem., 26: 16-20 (1983), describe a study wherein a series of 7-substituted mitomycin C's and porfiromycins were prepared and screened in standard anti-tumor systems. Certain of the analogues showed better activity than mitomycin C against various tumors, with some less leukopenic and some more leukopenic than the mitomycin C. The authors describe the selection of the 7 position for substitution with the 2-substituted-ethyl analogues because position 7 controls the reduction of the quinone ring, thereby offering an opportunity to gain selectivity between normal cells and certain cancer cells.
Suami, S. et al., J. Med. Chem., 27: 701-708 (1984), prepared a series of 30 different phenyl-substituted mitomycin C analogues, the phenyl substitution being at the 7 position. Seven of the compounds prepared were disclosed as clearly superior to mitomycin C in activity against P-388 murine leukemia.
It is also known from Suami T. et al., J. Med. Chem., 22, No. 3: 247-250 (1979), that N-(2-chloroethyl)-N-nitrosocarbamoyl derivatives of glycosylamines, including three disaccharide derivatives, exhibited strong anti-tumor activity against Leukemia 1210 in mice. Further, it has been demonstrated that glucopyranose derivatives of N-nitrosoureas possess immunogenic and marrow sparing properties (Anderson et al., Cancer Research 35, 761-765 (March 1975); Panasci, et al., J. Clin. Invest., Vol. 64, 1103-1111 (October 1979)).
Thus, as may be seen from the above disclosures, research has continued in an effort to synthesize and isolate analogues of the mitomycins which have comparable anti-neoplastic capability, but, at the same time, are less toxic to the animal system than the parent compound.